bims-mitrat 2024-12-01 papers

bims-mitrat

Biomed News

on Mitochondrial transplantation and transfer

Issue of 2024–12–01
twelve papers selected by
Gökhan Burçin Kubat, Gulhane Health Sciences Institute

Mitochondria: the epigenetic regulators of ovarian aging and longevity.
Unveiling the power of mitochondrial transfer in cancer progression: a perspective in ovarian cancer.
Mechanism and prospects of mitochondrial transplantation for spinal cord injury treatment.
Mitochondrial calcium uptake declines during aging and is directly activated by oleuropein to boost energy metabolism and skeletal muscle performance.
Effects of Hyperthermia and Acidosis on Mitochondrial Oxidative Phosphorylation.
Nanoparticle shape is the game-changer for blood-brain barrier crossing and delivery through tunneling nanotubes among glioblastoma cells.
ER-tethered stress sensor CREBH regulates mitochondrial unfolded protein response to maintain energy homeostasis.
Chronic alcohol consumption exacerbates ischemia-associated skeletal muscle mitochondrial dysfunction in a murine model of peripheral artery disease.
Reactive oxygen species in skeletal muscle injury, fatigue, regeneration and ageing: In memory of John Faulkner.
Altered Mitochondrial Unfolded Protein Response and Protein Quality Control promote oxidative distress in Down Syndrome brain.
Decreased mitochondrial transcription factor A and mitochondrial DNA copy number promote cyclin-dependent kinase inhibitor 1A expression and reduce tumorigenic properties of colorectal cancer cells.
Muscle regeneration and muscle stem cells in metabolic disease.

Front Endocrinol (Lausanne). 2024 ;15 1424826

Mitochondria: the epigenetic regulators of ovarian aging and longevity.

Shalini Mani, Vidushi Srivastava, Chesta Shandilya, Aditi Kaushik, Keshav K Singh.

  Ovarian aging is a major health concern for women. Ovarian aging is associated with reduced health span and longevity. Mitochondrial dysfunction is one of the hallmarks of ovarian aging. In addition to providing oocytes with optimal energy, the mitochondria provide a co-substrate that drives epigenetic processes. Studies show epigenetic alterations, both nuclear and mitochondrial contribute to ovarian aging. Both, nuclear and mitochondrial genomes cross-talk with each other, resulting in two ways orchestrated anterograde and retrograde response that involves epigenetic changes in nuclear and mitochondrial compartments. Epigenetic alterations causing changes in metabolism impact ovarian function. Key mitochondrial co-substrate includes acetyl CoA, NAD+, ATP, and α-KG. Thus, enhancing mitochondrial function in aging ovaries may preserve ovarian function and can lead to ovarian longevity and reproductive and better health outcomes in women. This article describes the role of mitochondria-led epigenetics involved in ovarian aging and discusses strategies to restore epigenetic reprogramming in oocytes by preserving, protecting, or promoting mitochondrial function.

Keywords:  aging; epigenetics; menopause; mitochondria; ovary

DOI:  https://doi.org/10.3389/fendo.2024.1424826
J Ovarian Res. 2024 Nov 23. 17(1): 233

Unveiling the power of mitochondrial transfer in cancer progression: a perspective in ovarian cancer.

Caixia Wang, Chuan Xie.

  Mitochondria are dynamic organelles integral to metabolic processes, coordination of essential biological pathways, and oncogenesis and tumor progression. Recent studies have revealed that mitochondria can be transferred between cells via multiple mechanisms, implicating their involvement in the pathogenesis and progression of ovarian cancer. This review provides a comprehensive analysis of intercellular mitochondrial transfer within the context of ovarian cancer and its tumor microenvironment. We also propose targeted pathways and therapeutic strategies that could be utilized to modulate diseases associated with mitochondrial transfer therapy. Finally, we examine recent advancements in this field and identify several unresolved questions.

Keywords:  Mitochondrial transfer; Ovarian Cancer; Targeted therapy; Tumor Microenvironment

DOI:  https://doi.org/10.1186/s13048-024-01560-8
Stem Cell Res Ther. 2024 Nov 28. 15(1): 457

Mechanism and prospects of mitochondrial transplantation for spinal cord injury treatment.

Qin Wang, Xin Wang, Zhizhong Shang, Long Zhao.

  Spinal cord injury (SCI) involves a continuous and dynamic cascade of complex reactions, with mitochondrial damage and dysfunction-induced energy metabolism disorders playing a central role throughout the process. These disorders not only determine the severity of secondary injuries but also influence the potential for axonal regeneration. Given the critical role of energy metabolism disturbances in the pathology of SCI, strategies such as enhancing mitochondrial transport within axons to alleviate local energy deficits, or transplanting autologous or allogeneic mitochondria to restore energy supply to damaged tissues, have emerged as potential approaches for SCI repair. These strategies also aim to modulate local inflammatory responses and apoptosis. Preclinical studies have initially demonstrated that mitochondrial transplantation (MT) significantly reduces neuronal death and promotes axonal regeneration following spinal cord injury. MT achieves this by regulating signaling pathways such as MAPK/ERK and PI3K/Akt, promoting the expression of growth-associated protein-43 (GAP-43) in neurons, and inhibiting the expression of apoptosis-related proteins like Grp78, Chop, and P-Akt, thereby enhancing the survival and regeneration of damaged neurons. Additionally, MT plays a role in promoting the expression of vascular endothelial growth factor, facilitating tissue repair, and reducing the secretion of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6. Furthermore, MT modulates neuronal apoptosis and inflammatory responses by decreasing the expression of p-JNK, a member of the MAPK family. In summary, by reviewing the detailed mechanisms underlying the cascade of pathological processes in SCI, we emphasize the changes in endogenous mitochondria post-SCI and the potential of exogenous MT in SCI repair. This review aims to provide insights and a basis for developing more effective clinical treatments for SCI.

Keywords:  Advancements; Mechanisms; Mitochondrial transplantation; Pathological cascade reactions; Spinal cord injury

DOI:  https://doi.org/10.1186/s13287-024-04077-5
Cell Metab. 2024 Nov 23. pii: S1550-4131(24)00417-0. [Epub ahead of print]

Mitochondrial calcium uptake declines during aging and is directly activated by oleuropein to boost energy metabolism and skeletal muscle performance.

Gaia Gherardi, Anna Weiser, Flavien Bermont, Eugenia Migliavacca, Benjamin Brinon, Guillaume E Jacot, Aurélie Hermant, Mattia Sturlese, Leonardo Nogara, Filippo Vascon, Agnese De Mario, Andrea Mattarei, Emma Garratt, Mark Burton, Karen Lillycrop, Keith M Godfrey, Laura Cendron, Denis Barron, Stefano Moro, Bert Blaauw, Rosario Rizzuto, Jerome N Feige, Cristina Mammucari, Umberto De Marchi.

  Mitochondrial calcium (mtCa2+) uptake via the mitochondrial calcium uniporter (MCU) couples calcium homeostasis and energy metabolism. mtCa2+ uptake via MCU is rate-limiting for mitochondrial activation during muscle contraction, but its pathophysiological role and therapeutic application remain largely uncharacterized. By profiling human muscle biopsies, patient-derived myotubes, and preclinical models, we discovered a conserved downregulation of mitochondrial calcium uniporter regulator 1 (MCUR1) during skeletal muscle aging that associates with human sarcopenia and impairs mtCa2+ uptake and mitochondrial respiration. Through a screen of 5,000 bioactive molecules, we identify the natural polyphenol oleuropein as a specific MCU activator that stimulates mitochondrial respiration via mitochondrial calcium uptake 1 (MICU1) binding. Oleuropein activates mtCa2+ uptake and energy metabolism to enhance endurance and reduce fatigue in young and aged mice but not in muscle-specific MCU knockout (KO) mice. Our work demonstrates that impaired mtCa2+ uptake contributes to mitochondrial dysfunction during aging and establishes oleuropein as a novel food-derived molecule that specifically targets MCU to stimulate mitochondrial bioenergetics and muscle performance.

Keywords:  MCU; MCUR1; aging; calcium signaling; endurance; energy; fatigue; mitochondria; polyphenols; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.1016/j.cmet.2024.10.021
J Appl Physiol (1985). 2024 Nov 27.

Effects of Hyperthermia and Acidosis on Mitochondrial Oxidative Phosphorylation.

Michael S Davis, Warwick M Bayly, Cristina M Hansen, Montana R Barrett, Cara A Blake.

  The intracellular environment of skeletal muscle can develop pronounced hyperthermia and acidosis during strenuous exercise, and these alterations in the typical intracellular conditions have been shown to alter mitochondrial respiration. However, the impact of these conditions on ATP synthesis is poorly understood. We used Thoroughbred racehorses to test the hypothesis that both hyperthermia and acidosis decrease the rate of ATP synthesis, but that athletic conditioning mitigates this loss of phosphorylation capacity. Isolated mitochondria were harvested from skeletal muscle before and after a 9-week racetrack conditioning program that increased whole-body aerobic capacity by 19%, and oxidative phosphorylation capacity was tested ex vivo under normothermic and hyperthermic conditions, as well as normal pH and acidic pH created by the addition of lactic acid. In unfit horses, hyperthermia caused a 30-55% decrease in the rate of ATP synthesis and loss of phosphorylation efficiency (P/O ratio decreased from 4.2 to 1.7 during maximal oxidative phosphorylation). Aerobic conditioning resulted in increased phosphorylation efficiency under hyperthermic conditions. Lactic acidosis had a small negative effect on ATP synthesis in unfit horses, but aerobic conditioning increased the sensitivity of isolated mitochondria to the deleterious effects of lactic acidosis. These data support a prominent role of hyperthermia in skeletal muscle fatigue during exercise, particularly in unfit subjects. However, acidosis may be a more important cause of failure of ATP synthesis in fit subjects.

Keywords:  ATP synthesis; Skeletal muscle; high-resolution respirometry; horse

DOI:  https://doi.org/10.1152/japplphysiol.00418.2024
Nanoscale. 2024 Nov 26.

Nanoparticle shape is the game-changer for blood-brain barrier crossing and delivery through tunneling nanotubes among glioblastoma cells.

Giulia Sierri, Ines Saenz-de-Santa-Maria, Antonio Renda, Marcus Koch, Patrizia Sommi, Umberto Anselmi-Tamburini, Mario Mauri, Alessia D'Aloia, Michela Ceriani, Domenico Salerno, Francesco Mantegazza, Chiara Zurzolo, Francesca Re.

Tunneling nanotubes (TNTs) are thin, dynamic, long membrane protrusions that allow intercellular exchanges of signaling clues, molecules and organelles. The presence of TNTs and their involvement as drug delivery channels have been observed in several types of cancer, including glioblastoma. Recently, increased attention has been directed toward nanoparticles (NPs) that can be transported in TNTs. However, few data are available on the role of physical parameters of nanoparticles, such as size, shape, charge and flexibility, in determining their transfer efficiency between cells by TNTs. Here, we focused our attention on NP shape, manufacturing spherical, discoidal and deformable negatively charged lipid-based NPs with sizes <120 nm and similar stiffness. The TNT-mediated transfer of NPs was investigated in 2D and 3D culture models of human glioblastoma cells. The permeability and biocompatibility of the blood-brain barrier (BBB) were also assessed. Results showed that discoidal NPs displayed the highest TNT-mediated transfer efficiency between cancer cells, with a maximum velocity of 69 nm s-1, and a higher endothelial permeability (1.29 × 10-5 cm min-1) across the BBB in an in vitro model. This depends on the NP shape because discoidal NPs have a larger surface area exposed to the flow along the TNT channel. Overall, the results suggest that the shape of NPs is the game-changer for more efficient TNT-mediated transfer between cancer cells, thus introducing a sustainable solution to improve the diffusion rate at which the NPs spread in the tumour microenvironment, opening the possibility of ameliorating drug distribution to difficult-to-reach cancer cell populations.

DOI: https://doi.org/10.1039/d4nr03174a
Proc Natl Acad Sci U S A. 2024 Dec 03. 121(49): e2410486121

ER-tethered stress sensor CREBH regulates mitochondrial unfolded protein response to maintain energy homeostasis.

Hyunbae Kim, Qi Chen, Donghong Ju, Neeraja Purandare, Xuequn Chen, Lobelia Samavati, Li Li, Ren Zhang, Lawrence I Grossman, Kezhong Zhang.

  The Mitochondrial Unfolded Protein Response (UPRmt), a mitochondria-originated stress response to altered mitochondrial proteostasis, plays important roles in various pathophysiological processes. In this study, we revealed that the endoplasmic reticulum (ER)-tethered stress sensor CREBH regulates UPRmt to maintain mitochondrial homeostasis and function in the liver. CREBH is enriched in and required for hepatic Mitochondria-Associated Membrane (MAM) expansion induced by energy demands. Under a fasting challenge or during the circadian cycle, CREBH is activated to promote expression of the genes encoding the key enzymes, chaperones, and regulators of UPRmt in the liver. Activated CREBH, cooperating with peroxisome proliferator-activated receptor α (PPARα), activates expression of Activating Transcription Factor (ATF) 5 and ATF4, two major UPRmt transcriptional regulators, independent of the ER-originated UPR (UPRER) pathways. Hepatic CREBH deficiency leads to accumulation of mitochondrial unfolded proteins, decreased mitochondrial membrane potential, and elevated cellular redox state. Dysregulation of mitochondrial function caused by CREBH deficiency coincides with increased hepatic mitochondrial oxidative phosphorylation (OXPHOS) but decreased glycolysis. CREBH knockout mice display defects in fatty acid oxidation and increased reliance on carbohydrate oxidation for energy production. In summary, our studies uncover that hepatic UPRmt is activated through CREBH under physiological challenges, highlighting a molecular link between ER and mitochondria in maintaining mitochondrial proteostasis and energy homeostasis under stress conditions.

Keywords:  ER-mitochondria contact; cell metabolism; michondrial UPR; transcriptional regulation; unfolded protein response

DOI:  https://doi.org/10.1073/pnas.2410486121
Biochim Biophys Acta Mol Basis Dis. 2024 Nov 23. pii: S0925-4439(24)00578-7. [Epub ahead of print]1871(2): 167584

Chronic alcohol consumption exacerbates ischemia-associated skeletal muscle mitochondrial dysfunction in a murine model of peripheral artery disease.

Emma Fletcher, Dimitrios Miserlis, Evlampia Papoutsi, Jennifer L Steiner, Bradley Gordon, Gleb Haynatzki, Pal Pacher, Panagiotis Koutakis.

   PURPOSE: Peripheral artery disease (PAD) causes ischemic mitochondriopathy-associated muscle damage, amplifying patient disability and mortality. Although alcohol and a high-fat diet enhance PAD predisposition and severity, their impact on PAD myopathy is unclear. Using our murine model of PAD, we investigated the combined effect of chronic alcohol and fat consumption on intramuscular oxidative stress and mitochondrial content, function, and quality control. The potential relationship between intramuscular aldehyde dehydrogenase 2 (ALDH2) content, oxidative stress and mitochondriopathy was also explored.
METHODS: Twenty-four male, 24 female, 8-month-old C57BL/6 J mice received high-fat-sucrose (HFS) or low-fat-sucrose (LFS) diets for 16-weeks, followed by either 20 % ethanol (EtOH) supplemented in the drinking water or continued water access for another 12-weeks (n = 12 mice/4 groups). The left femoral artery was ligated to induce hindlimb ischemia (HLI), and mice 4-weeks post-ligation were euthanized.
RESULTS: Chronic HLI was associated with an ischemic muscle mitochondriopathy, which was exacerbated by concurrent HFS and EtOH feeding. Intramuscular ALDH2 was also reduced in mice consuming HFS + EtOH, particularly in the ischemic limb, but increased in their LFS + EtOH-consuming counterparts. Moreover, reduced ALDH2 was strongly correlated with markers of oxidative stress and mitochondrial dysfunction.
CONCLUSIONS: ALDH2 could be a promising therapeutic target to optimize intramuscular mitochondrial function in PAD patients, particularly those who habitually consume a diet high in fat and alcohol.

Keywords:  Aldehyde dehydrogenase-2; Chronic alcohol and fat consumption; Hindlimb ischemia; Intramuscular mitochondrial dysfunction; Oxidative stress; Peripheral artery disease

DOI:  https://doi.org/10.1016/j.bbadis.2024.167584
Free Radic Biol Med. 2024 Nov 27. pii: S0891-5849(24)01080-3. [Epub ahead of print]

Reactive oxygen species in skeletal muscle injury, fatigue, regeneration and ageing: In memory of John Faulkner.

Hongyang Xu, Jacob L Brown, Shylesh Bhaskaran, Holly Van Remmen.

  One of the most critical factors impacting healthspan in the elderly is the loss of muscle mass and function, clinically referred to as sarcopenia. Muscle atrophy and weakness lead to loss of mobility, increased risk of injury, metabolic changes and loss of independence. Thus, defining the underlying mechanisms of sarcopenia is imperative to enable the development of effective interventions to preserve muscle function and quality in the elderly and improve healthspan. Over the past few decades, understanding the roles of mitochondrial dysfunction and oxidative stress has been a major focus of studies seeking to reveal critical molecular pathways impacted during aging. In this review, we will highlight how oxidative stress might contribute to sarcopenia by discussing the impact of oxidative stress on the loss of innervation and alteration in the neuromuscular junction (NMJ), on muscle mitochondrial function and atrophy pathways, and finally on muscle contractile function.

Keywords:  Aging; Mitochondria; Neuromuscular Junction; Sarcopenia; Skeletal Muscle

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.11.046
Free Radic Biol Med. 2024 Nov 23. pii: S0891-5849(24)01077-3. [Epub ahead of print]

Altered Mitochondrial Unfolded Protein Response and Protein Quality Control promote oxidative distress in Down Syndrome brain.

Simona Lanzillotta, Daniel Esteve, Chiara Lanzillotta, Antonella Tramutola, Ana Lloret, Elena Forte, Vito Pesce, Anna Picca, Fabio Di Domenico, Marzia Perluigi, Eugenio Barone.

  Down Syndrome (DS) is a genetic disorder caused by the presence of an extra copy of chromosome 21, and leading to various developmental and cognitive defects. A critical feature of DS is the occurrence of oxidative distress particularly in the brain, which exacerbates neurodevelopmental processes. Mitochondria play a crucial role in cell energy metabolism and their impairment is one of the major causes of oxidative distress in several pathologies. Hence, this study investigates mitochondrial proteostasis by the mean of the mitochondrial Unfolded Protein Response (UPRmt) and the mitochondrial protein quality control (MQC) mechanisms in the context of DS, focusing on their implications in redox homeostasis in brain development. We analyzed key UPRmt markers and mitochondrial function in the frontal cortex isolated fromTs2Cje mice, a model for DS, across different developmental stages. Our results demonstrate significant alterations in UPRmt markers, particularly at postnatal day 0 (P0) and 1 month (1M). These changes indicate early UPRmt activation, primarily driven by the ATF5/GRP75 axis, although compromised by reduced levels of other components. Impaired UPRmt correlates with decreased mitochondrial activity, evidenced by reduced oxygen consumption rates and altered expression of OXPHOS complexes. Additionally, elevated oxidative stress markers such as 3-nitrotyrosine (3-NT), 4-hydroxynonenal (HNE), and protein carbonyls (PC) were observed, linking mitochondrial dysfunction to increased oxidative damage. Defects of MQC, including disrupted biogenesis, increased fission, and the activation of mitophagy were evident mostly at P0 and 1M consistent with UPRmt activation. Principal Component Analysis revealed distinct phenotypic differences between Ts2Cje and control mice, driven by these molecular alterations. Our findings underscore the critical role of UPRmt and MQC in DS brain development, highlighting potential therapeutic targets to mitigate mitochondrial dysfunction and oxidative distress, thereby alleviating some of the neurodevelopmental and cognitive impairments associated with DS.

Keywords:  Down Syndrome; UPRmt; brain development; mitochondrial metabolism; oxidative stress

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.11.043
Discov Oncol. 2024 Nov 24. 15(1): 701

Decreased mitochondrial transcription factor A and mitochondrial DNA copy number promote cyclin-dependent kinase inhibitor 1A expression and reduce tumorigenic properties of colorectal cancer cells.

Jessika Buchwaldt, Tania Fritsch, Monika Hartmann, Hagen Roland Witzel, Michael Kloth, Wilfried Roth, Katrin E Tagscherer, Nils Hartmann.

   PURPOSE: Colorectal cancer is one of the most common and deadliest cancer types worldwide. In the last years, changes in the mitochondrial DNA (mtDNA) copy number have been described to correlate with the prognostic outcome for colorectal cancer patients by impacting different tumorigenic properties. One key regulator of mtDNA is the mitochondrial transcription factor A (TFAM) that acts as a limiting factor of mtDNA copy number. Here, we investigated the effect of TFAM deficiency on mtDNA and tumorigenic properties in the human colorectal cancer cell line SW480.
METHODS: TFAM expression was stably downregulated in the colorectal cancer cell line SW480 using the CRISPR-Cas9 approach. To dissect the molecular alterations induced by deletion of TFAM, RNA sequencing and gene set enrichment analysis was performed on TFAM-wild-type and TFAM-deficient SW480 cells. Functional consequences of TFAM downregulation were assessed in cellular assays.
RESULTS: We showed that TFAM deficiency leads to decreased mtDNA copy number and reduced expression of mtDNA-encoded genes. TFAM-deficient cells also revealed higher activity of senescence-associated β-galactosidase and decreased cell growth parameters. Moreover, RNA sequencing showed that the expression of cyclin dependent kinase inhibitor 1A (CDKN1A/p21) is significantly increased in TFAM-deficient cells.
CONCLUSION: Our results suggest that TFAM-induced changes of the mitochondrial genome lead to upregulated CDKN1A/p21 expression in colorectal cancer cells identifying p21 as a new possible linker between mitochondria and nucleus.

Keywords:  Cell proliferation; Colon cancer; Cyclin-dependent kinase inhibitor 1A (CDKN1A/p21); Mitochondria; Mitochondrial DNA (mtDNA); Senescence; Transcription factor A mitochondrial (TFAM)

DOI:  https://doi.org/10.1007/s12672-024-01538-4
Free Radic Biol Med. 2024 Nov 22. pii: S0891-5849(24)01075-X. [Epub ahead of print]

Muscle regeneration and muscle stem cells in metabolic disease.

Jin D Chung, Enzo R Porrello, Gordon S Lynch.

  Skeletal muscle has a high regenerative capacity due to its resident adult muscle stem cells (MuSCs), which can repair damaged tissue by forming myofibres de novo. Stem cell dependent regeneration is critical for maintaining skeletal muscle health, and different conditions can draw heavily on MuSC support to preserve muscle function, including metabolic diseases such as diabetes. The global incidence and burden of diabetes is increasing, and skeletal muscle is critical for maintaining systemic metabolic homeostasis and improving outcomes for diabetic patients. Thus, poor muscle health in diabetes, termed diabetic myopathy, is an important complication that must be addressed. The health of MuSCs is also affected by diabetes, responsible for the poor muscle regenerative capacity and contributing to the functional decline in diabetic patients. Here, we review the impact of diabetes and metabolic disease on MuSCs and skeletal muscle, including potential mechanisms for impaired muscle regeneration and MuSC dysfunction, and how these deficits could be addressed.

Keywords:  Diabetes; Metabolic disease; Metabolism; Muscle regeneration; Muscle stem cell

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.11.041